Impaired insulin-regulated glucose clearance by skeletal muscle is an early event in the development of non-insulin dependent diabetes mellitus (NIDDM), a potentially lethal condition, which affects over 5 million people at estimated costs of over $20 billion annually in the U.S. alone. Several lines of evidence indicate that reduced expression of hexokinase II (HKII) activity may be responsible for this. The goal of this proposal is to identity novel orally-administered therapeutic agents to stimulate the expression of the HKII gene in order to better control blood glucose levels in NIDDM. To facilitate drug discovery, we will develop an automated high-throughput cell-based drug screen using skeletal muscle cells stably transfected with a luciferase reporter vector controlled by the 5'-regulatory elements of the HKII gene. This approach permits rapid evaluation of large natural product libraries or collections of compounds, making it possible to consider leads representing as much molecular diversity as possible. In Phase I we will prepare the reporter cell line, and in preparation for lead follow-up studies, will investigate a novel cell culture system for studying the regulation of glucose uptake in skeletal muscle. The drug screen and follow-up studies will be performed in Phase II. PROPOSED COMMERCIAL APPLICATION: Activators of hexokinase II gene expression identified as a result of this project have significant potential for the treatment of non-insulin dependent diabetes mellitus. Because of the very high incidence of this disease, and current lack of efficacious therapies, an effective drug of this type would very likely generate revenues in excess of $1 billion annually.